Structure and functional analysis of the IGF-II/IGF2R interaction

被引：87

作者：

Brown, James ^{[1
]}

Delaine, Carlie

Zaccheo, Oliver J.

Siebold, Christian ^{[1
]}

Gilbert, Robert J.

van Boxel, Gijs ^{[1
]}

Denley, Adam

Wallace, John C.

Hassan, A. Bassim

Forbes, Briony E.

Jones, E. Yvonne ^{[1
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Canc Res UK Receptor Struct Res Grp, Oxford OX3 7BN, England

来源：

EMBO JOURNAL | 2008年 / 27卷 / 01期

基金：

英国医学研究理事会;

关键词：

growth factor receptor; IGF-II; IGF system; protein crystallography; tumour suppression;

D O I：

10.1038/sj.emboj.7601938

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Embryonic development and normal growth require exquisite control of insulin-like growth factors (IGFs). In mammals the extracellular region of the cation-independent mannose-6-phosphate receptor has gained an IGFII-binding function and is termed type II IGF receptor (IGF2R). IGF2R sequesters IGF-II; imbalances occur in cancers and IGF2R is implicated in tumour suppression. We report crystal structures of IGF2R domains 11-12, 11-12-13-14 and domains 11-12-13/ IGF-II complex. A distinctive juxtaposition of these domains provides the IGF-II binding unit, with domain 11 directly interacting with IGF-II and domain 13 modulating binding site flexibility. Our complex shows that Phe19 and Leu53 of IGF-II lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2Rs. Mutagenesis analyses confirm this IGF-II 'binding-hotspot', revealing that IGF-binding proteins and IGF2R have converged on the same high-affinity site.

引用

页码：265 / 276

页数：12

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